Expression levels of blood microRNAs as biomarker of cognitive decline due to Alzheimer's disease

Studies investigating differential miRNAs expression levels in patients with Alzheimer’s disease (AD) abounded in the last decades and catalysed the interest towards miRNAs as novel non-invasive biomarkers of AD. Chapter 1 provides an overview of AD’s pathogenesis, discusses the evolution of the disease’s definition, and introduces miRNAs. In Chapter 2, a systematic review and a P-value based meta-analysis of 107 studies investigate miRNA expression levels in AD patients. This leads to a prioritisation of 25, 32 and 5 dysregulated miRNAs at study-wide significance in the brain, the blood and the cerebrospinal fluid (CSF) of AD patients, respectively. A pathway enrichment analysis for the top dysregulated miRNAs in the brain confirms their role in regulating biological functions implicated in AD. In Chapter 3, expression levels of the 32 dysregulated miRNAs in the blood and 6 top dysregulated miRNAs in the brain of AD patients, are assessed using real-time quantitative polymerase chain reaction in the blood of cognitively healthy individuals from the CHARIOT-PRO cohort. Low performers on the total Repeatable Battery for the Assessment of Neuropsychological Status scale show downregulation of six miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p). Pathway enrichment analysis highlights involvement in pathways initiating early pathogenetic changes in AD. Finally, in chapter 4, whole-genome sequencing data from the Alzheimer’s Disease Neuroimaging Initiative is used to perform an association analysis between polymorphisms within the six miRNAs’ genes and CSF biomarkers of neurodegeneration. A functional annotation of significant variants highlights expression quantitative trait loci, location in enhancer regions and alterations in the binding sites of transcription factors regulating neuronal function. The association of variants located within the same miRNA gene with different markers of neurodegeneration reveals a positive correlation between members of the amyloid cascade and microglial activation in the CSF. The final chapter highlights the clinical relevance of these findings and discusses future perspectives.Open Acces

Patients with geriatric syndromes and anti-amyloid therapies: lack of consideration? An exploratory analysis of the literature.

INTRODUCTION Patients who should benefit from anti-amyloid therapies (AAT) are found across all geriatric settings. Yet, it remains unclear how the use of AAT in patients with geriatric syndromes, such as frailty and polypharmacy, has so far been discussed in the literature. METHODS Articles on aducanumab, gantenerumab, lecanemab, donanemab, crenezumab, solanezumab were retrieved in MEDLINE from inception to July 2023. For each article, identified geriatric relevant terms were assigned to five discussion contexts (eligibility of AAT study population, safety, prescription, patient clinical profile, alternative outcomes measurement). Article type and the involvement of geriatric healthcare professionals as an author were further extracted. RESULTS Out of 538 articles, 23 (4.27%) were published in journals from the geriatric category, 44 (8.18%) included an author affiliated with a geriatric institution. One hundred and sixteen (21.56%) articles included at least one geriatric relevant term, which were mostly discussed in the context of safety and eligibility. Articles mentioning geriatric syndromes were more frequently authored by a geriatric healthcare professional (p = 0.044). DISCUSSION The use of AAT in patients with geriatric syndromes has so far received poor attention in the literature raising concerns on their use in this patient group. The involvement of geriatric healthcare professionals in future studies may increase the relevance of AAT research in patients with geriatric syndromes

How to Study Child Sexual Abuse Within the Institutional Framework? The Experience of the Catholic Church in Poland

Sexual abuse as a manifestation of personality disorders and a crime is shaped and committed in a specific social environment. The Institute for Catholic Church Statistics was the first in Poland to undertake systematic research on the problem of child sexual abuse. The scope of this research concerns the acts committed within Catholic organizations by priests and religious. In this chapter, we present Polish research on abuse and characterize the organizational framework of the Catholic Church in Poland. We highlight the public importance of research on child sexual abuse by priests. The focus of the chapter, however, is devoted to the methodological issues of quantitative sociological research on the sexual abuse of minors within Catholic organizations. We discuss the basic assumptions, methods and scope of collected data that concerns Poland. In an accessible and understandable way for a reader who has no knowledge of social sciences, we ­explain how the facts of child abuse by priests and religious are studied in Poland

Triptych

Our desire is for this publication to be at the intersection of architecture and neuroscience; where the convergence of architecture (the art of building) and neuroscience (the biology of the brain) is aesthetic experience. The biology of the brain returns architecture to a biological foundation of mood and atmosphere. As architecture students, the more we learn about architecture in terms of a sensory experience, the better we can design. Just as we learn architecture by doing it, flickering between theory and practice, by dancing between thinking and feeling, so can we learn any subject. This publication is the product of a five month graduate seminar in which we studied introductory literature in the art and science of spatial experience and investigations into specific questions raised within our discussions. The topics of research are extensions of specific students curiosity, which has research merit relative to the collective’s inquiries. Our deepest gratitude to our advisor, Professor Bob Condia. We were fortunate enough to have a professor who gave us the freedom to explore on our own and guide us. Professor Bob Condia taught us how to question thoughts and express ideas through critical thinking and communicationhttps://newprairiepress.org/ebooks/1013/thumbnail.jp

Association of chronic pain with biomarkers of neurodegeneration, microglial activation and inflammation in the CSF and impaired cognitive function

ObjectivesDebate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).MethodsParticipants were classified using the ATN classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, ANCOVA models identified differences in CSF levels of Aβ1‐42, ptau181, t‐tau, sTREM2 and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analysed. Linear mixed‐effect models examined longitudinal changes.ResultsThe study included 995 individuals with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non‐Alzheimer's pathophysiology (SNAP) and chronic pain showed increased CSF levels of t‐tau and sTREM2. Chronic pain was associated with increased TNF‐α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid positive and neurodegeneration negative chronic pain patients showed higher memory function cross‐sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group.Interpretationour study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm those findings.This article is protected by copyright. All rights reserved.</jats:sec

Increased brain age in adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the most common genetic obesity syndrome, with associated learning difficulties, neuroendocrine deficits, and behavioural and psychiatric problems. As the life expectancy of individuals with PWS increases, there is concern that alterations in brain structure associated with the syndrome, as a direct result of absent expression of PWS genes, and its metabolic complications and hormonal deficits, might cause early onset of physiological and brain aging. In this study, a machine learning approach was used to predict brain age based on grey matter (GM) and white matter (WM) maps derived from structural neuroimaging data using T1-weighted magnetic resonance imaging (MRI) scans. Brain-predicted age difference (brain-PAD) scores, calculated as the difference between chronological age and brain-predicted age, are designed to reflect deviations from healthy brain aging, with higher brain-PAD scores indicating premature aging. Two separate adult cohorts underwent brain-predicted age calculation. The main cohort consisted of adults with PWS (n = 20; age mean 23.1 years, range 19.8-27.7; 70.0% male; body mass index (BMI) mean 30.1 kg/m2, 21.5-47.7; n = 19 paternal chromosome 15q11-13 deletion) and age- and sex-matched controls (n = 40; age 22.9 years, 19.6-29.0; 65.0% male; BMI 24.1 kg/m2, 19.2-34.2) adults (BMI PWS vs. control P = .002). Brain-PAD was significantly greater in PWS than controls (effect size mean ± SEM +7.24 ± 2.20 years [95% CI 2.83, 11.63], P = .002). Brain-PAD remained significantly greater in PWS than controls when restricting analysis to a sub-cohort matched for BMI consisting of n = 15 with PWS with BMI range 21.5-33.7 kg/m2, and n = 29 controls with BMI 21.7-34.2 kg/m2 (effect size +5.51 ± 2.56 years [95% CI 3.44, 10.38], P = .037). In the PWS group, brain-PAD scores were not associated with intelligence quotient (IQ), use of hormonal and psychotropic medications, nor severity of repetitive or disruptive behaviours. A 24.5 year old man (BMI 36.9 kg/m2) with PWS from a SNORD116 microdeletion also had increased brain PAD of 12.87 years, compared to 0.84 ± 6.52 years in a second control adult cohort (n = 95; age mean 34.0 years, range 19.9-55.5; 38.9% male; BMI 28.7 kg/m2, 19.1-43.1). This increase in brain-PAD in adults with PWS indicates abnormal brain structure that may reflect premature brain aging or abnormal brain development. The similar finding in a rare patient with a SNORD116 microdeletion implicates a potential causative role for this PWS region gene cluster in the structural brain abnormalities associated primarily with the syndrome and/or its complications. Further longitudinal neuroimaging studies are needed to clarify the natural history of this increase in brain age in PWS, its relationship with obesity, and whether similar findings are seen in those with PWS from maternal uniparental disomy

Prospective Study of Ageing Trajectories in the European DO-HEALTH Study.

INTRODUCTION Ageing trajectories range from delayed ageing with extended health to accelerated ageing, with an increased risk of frailty. We evaluated the prevalence and prospective change between health states among community-dwelling European older adults. METHODS This prospective study is a secondary analysis of DO-HEALTH, a randomized trial that included adults aged 70 years and older across 5 European countries. Healthy agers (HA) fulfilled the Nurses' Health Study healthy ageing criteria and accelerated agers were non-HA being at least pre-frail according to the Fried frailty criteria. We assessed the proportion of participants changing between health states over 4 assessments and evaluated the odds of changing to a more favourable category. To increase reliability and avoid regression to the mean, we averaged the first 2 years and compared them to the average of the last 2 years. RESULTS Of 2,157 participants, 12.4% were excluded for meeting both healthy ageing and pre-frailty criteria simultaneously. Among the remaining 1,889 participants (mean age 75.1 years, 60.9% female), 23.1% were initially HA, 44.4% were non-HA but not pre-frail, and 32.6% were pre-frail or frail. Subsequently, 65.3% remained in the same health state, 12.0% improved to a healthier state, and 22.8% progressed to a less advantageous state. After adjusting for sex, study centre, treatment, and body mass index, each year of age was associated with 6% lower odds of improving health states. Women had 35% higher odds than men of following a disadvantageous trajectory. CONCLUSION We observed dynamic trajectories of ageing where transitioning to a healthier state became less likely with advancing age and among women

Seeing the forest through the trees: prioritising potentially functional interactions from Hi-C.

Eukaryotic genomes are highly organised within the nucleus of a cell, allowing widely dispersed regulatory elements such as enhancers to interact with gene promoters through physical contacts in three-dimensional space. Recent chromosome conformation capture methodologies such as Hi-C have enabled the analysis of interacting regions of the genome providing a valuable insight into the three-dimensional organisation of the chromatin in the nucleus, including chromosome compartmentalisation and gene expression. Complicating the analysis of Hi-C data, however, is the massive amount of identified interactions, many of which do not directly drive gene function, thus hindering the identification of potentially biologically functional 3D interactions. In this review, we collate and examine the downstream analysis of Hi-C data with particular focus on methods that prioritise potentially functional interactions. We classify three groups of approaches: structural-based discovery methods, e.g. A/B compartments and topologically associated domains, detection of statistically significant chromatin interactions, and the use of epigenomic data integration to narrow down useful interaction information. Careful use of these three approaches is crucial to successfully identifying potentially functional interactions within the genome.Ning Liu, Wai Yee Low, Hamid Alinejad, Rokny, Stephen Pederson, Timothy Sadlon, Simon Barry, and James Bree

Prevalence of polypharmacy in community-dwelling older adults from seven centres in five European countries : A cross-sectional study of DO-HEALTH

Objective To investigate the prevalence of polypharmacy and characteristics associated with polypharmacy in older adults from seven European cities. Design Cross-sectional study of baseline data from DO-HEALTH. Setting and participants DO-HEALTH enrolled 2157 community-dwelling adults age 70 and older from seven centres in Europe. Participants were excluded if they had major health problems or Mini-Mental State Examination Score <24 at baseline. Primary outcome measures Extensive information on prescription and over-the-counter medications were recorded. Polypharmacy was defined as the concomitant use of five or more medications, excluding vitamins or dietary supplements. Bivariate and multivariable logistic regression was used to test the association of sociodemographic factors (age, sex, years of education, living situation and city) and health-related indicators (number of comorbidities, cognitive function, frailty status, body mass index (BMI), prior fall, self-rated health and smoking status) with polypharmacy. Results 27.2% of participants reported polypharmacy ranging from 16.4% in Geneva to 60.8% in Coimbra. In the multivariable logistic regression analyses, older age (OR 1.07; 95% CI 1.04 to 1.10), greater BMI (OR 1.09; 95% CI 1.06 to 1.12) and increased number of comorbidities (OR 2.13; 95% CI 1.92 to 2.36) were associated with polypharmacy. Women were less likely to report polypharmacy than men (OR 0.65; 95% CI 0.51 to 0.84). In comparison to participants from Zurich, participants from Coimbra were more likely to report polypharmacy (OR 2.36; 95% CI 1.56 to 3.55), while participants from Geneva or Toulouse were less likely to report polypharmacy ((OR 0.36; 95% CI 0.22 to 0.59 and OR 0.64; 95% CI 0.42 to 0.96), respectively). Living situation, smoking status, years of education, prior fall, cognitive function, self-rated health and frailty status were not significantly associated with polypharmacy. Conclusion Polypharmacy is common among relatively healthy older adults, with moderate variability across seven European cities. Independent of several confounders, being a woman, older age, greater BMI and greater number of comorbidities were associated with increased odds for polypharmacy. Trial registration number NCT01745263